Basically substituted ethers of pyridyl carbinols



Patented Aug. 5, 1952 UNITED STATES ATENT' OFFICE BASICALLY SUBSTITUTED ETHERS OF PYRIDYL CARBINOLS Robert S. Shelton, Mariemont, and Charles H. Tili'ord, Cincinnati, Ohio, assignors to The Wm. S. Merrell Company, Cincinnati, Ohio, a corporation of Delaware No Drawing. Application June 6, 1951,

Serial No. 230,263 a in which R. is a hydrogen atom or an alkyl radical having one or two carbon atoms, R" likewise is a hydrogen atom or an alkyl radical having one or two carbon atoms, n is an integer from 1 to 3, -NR2 is a dimethylamino, diethylamino, methylethylamino, 4-morpholino, 1- piperidino, or l-pyrrolidino group and is a saturated monocyclic or bicyclic carbon ring system having from 6' to 10 carbon atoms attached to the 2- or the 4-position of the pyridine nucleus.

These compounds can be prepared by methods described in our copending application, Serial No. 31,827, filed June 8, 1948, of which application this application is a continuation-in-part. According to these methods,- an appropriate pyridyl carbinol in the form of its sodium salt is allowed to react with the desired basic alkyl chloride. The pyridyl carbinol can conveniently be obtained by reacting a suitable carbocyclic ketone with pyridine or a suitable pyridine derivative" in the presence of a condensing agent, such as metallic aluminum or magnesium and a small amount of mercuric chloride. Ketones which are of particular interest as starting materials are camphor, fenchcne, menthone, thujone and cyclohexanone. Pyridine derivatives which are of particular value are alpha-, betaand gamma-picoline, alphaand gamma-ethylpyridine, 2,3-, 2,4- and 2,6-dimethylpyridine and 2-ethyl-5-methylpyridine.

These ethers are generally isolated as light colored or colorless viscous oils which may crystallize on standing. They are readily converted to water soluble salts of acids such as hydrochloric, sulfuric, maleic, fumaric, succinic acids. The latter salts of dibasic organic acids are particularly easy to crystallize and purify and lend themselves readily to the preparation of syrups, elixirs, or tablets for therapeutic use.

The compounds will. ordinarily be adminextracts were uncolored.

istered orally but parenteral administration is also possible.

The pharmacological action of these compounds is exemplified by the fumarate salt of -2 (2 'y picolyl) 2 (,8 diethylaminoethoxy) .camphane which has an oral 111350 in mice of 340 mg./kg. and an intravenous LD50 in mice of 62 mg./kg. When a 10 mg./kg. subcutaneous dose of this compound is administered to mice under mild narcosis with Evipal (5-cyclohexenyl- 1,5-dimethyl .barbituric acid) the effect of the barbiturate is potentiated by 50 to as evidenced by increased sleeping time.

The preparation of these compounds is further revealed by the following examples:

Example I.--2(2--y-picolyl)-2-(p-diethylaminoethory) camphane A. PREPARATION OF 1-(2-7-PICOLYLl-CA'RNEOL (f/H: CH3 0 $H;

A1 l CHs-OHa CHF'CH:

p (H8012) N N OH CH:

In a three-liter, three-neck flask equipped with a stirrer, reflux condenser and a dropping funnel were placed g. of aluminum granules, 50 g. of 'y-picoline, 0.5 g. of mercuric chloride and a few crystals of iodine. This mixture was heated to reflux and a, mixture of 10 g. ofcamphor dissolved in 50 g. of q-picoline was added. The reisulting mixture was heated to reflux for 30 minutes until the reaction had been initiated. Then, 750 g. of c-amphor, dissolved in 831 g. of y-p-icoline, was added dropwise during a period of about 2 hours. The mixture was heated to reflux with stirring for approximately 60 hours.

The mixture. was diluted with 500 cc. of toluene and then washed (with cooling) with one liter of 15% sodium hydroxide solution. The layers were separated, the. aqueous alkaline layer being discarded and the toluene layer being washed once with water. The toluene layer was then extracted with 10% hydrochloric acid until the The toluene layer was discarded. The aqueous acidic extract was washed once with ether, then made alkaline (with cooling) to phenolphthalein by the addition of solid sodium hydroxide. The oil which separated was extracted with benzene. The benzene was removed by distillation under reduced pressure. The crude product was distilled'at low pressure toyield 484 g. (39.5%, based on camthen filtered.

B. PREPARATION OF THE BASIC ETHER A toluene solution or p-diethylaminoethyl chloride was prepared from p-diethylaminoethyl chloride hydrochloride (665 g.) by dissolving the salt in 800 cc. of water, adding solid sodium hydroxide (185 g.) with cooling, and then extracting the amino chloride with several portions of toluene. The toluene extracts were combined and dried with anhydrous magnesium sulfate,

Sodium metal (44.5 g.) was melted under 850 cc. of dry boiling toluene. With stirring, at solution of 1-(2- -picolyD-borneol (474 g.) in 850 cc.

.of toluene was added to the finely divided suspension of molten sodium during a period of 2 hours. The resulting mixture was heated to reflux for about 16 hours, or until all of the sodium had reacted.

The dry toluene solution of fl-diethylaminoethyl chloride was then added dropwise during a period of about 3 hours. The mixture was heated to reflux for about 16 hours. The solid which had separated was removed by filtration. The toluene was removed from the filtrate by distillation under reduced pressure, after which the residual oil was distilled at low pressure. The pure 2- (2-y-picolyl) -2-(2-diethylaminoethoxy) camphane amounted to 441 g. (66%), B. P. 142- 147 C. (uncorr.) at 0.25 mm., 11 1.5090.

C. PREPARATION OF THE 'FUMARATE SALT (225 g.) was recrystallized from acetone to give 4 183 g. (60%) of pure 2-(2- -picolyD-2-(2-diethylaminoethoxy)camphane Iumarate, M. P. 121-123 C. (corr.). Analysis of the product: Calcd. for C2sH4oO5N2I C. 67.79%; H, 8.75%; N, 6.08%. Found: C, 68.00%, 67.91%; H, 8.88, 8.84%; N, 5.87%, 5.90%.

Example II .2- (z- -picolyl) -2- (fl-dimethylaminoethomy) camphane This compound is obtained from the reaction of 1-(2- -picolyl)borneol and p-dimethylaminoethyl chloride using procedure IB above. The product is obtained as a pale yellow oil, B. P. 140- 145 at about 0.25 mm.

Example III .2- (z-y-picolyl) -2- (p-diethylaminoethoxy) -1,3,3-trimethylnorcamphane By reacting fenchone with a-picoline according to procedure IA above there is obtained 2-(2- -picolyl) -1,3,3 trimethyl-2-norcamphanol as a yellow oil, '3. P. -120 at 0.2 mm. The reaction of this material with fi-diethylaminoethyl chloride according to procedurem above gives the desired ether as a viscous oil, B. P. l45-150 at 0.2 mm. 4

Example I V.3- [2- (4,6-dimethylpyridyl) 3- (,B-dlmethylaminoethoxy) menthane By reacting menthone with a -lutidine according to procedure IA above there is obtained 3- [2- (4,5-dimethylpyridyl) l-3-menthano1 as a yellow oil. This compound reacted with p-dimethylaminoethyl chloride by procedure 1B above gives the basic ether, B. P. ISO-160 at 0.3 mm.

Example V. Z-(Z-pyridyl)-2-(p-dimethylaminoethoxy) campha'ne. a- (2-pyridyl) -bornyl alcohol was prepared by the procedure of Example I, using camphor as the ketone. The product was collected at -2" C./0.1 mm. The hydrochloride melted at 209-210 C. From this alcohol there was obtained by the etherification procedure of Example I the aminoether distilling at 134-138 C./0.2 mm. The melting point of the dihydrochloride was 146-148 C.

Erample VI .2 (Z-pyridyl) -2- (fi-diethylaminoethomy) -camphane From a-(2-pyridyl)bornyl alcohol and p-diethylaminoethyl chloride by the procedure of Example 13 the amino ether, B. P. 150-54 C./0.3 mm. was obtained which was converted to 2-(2- pyridyl) 2 (B diethylaminoethoxy) camphane fumarate, M. P. 144-46 C.

Example VII. 2- (Z-pyridyl) -2- (fl-dimethylaminoethozry) 1,3,3 trimethylnorcamphane. a- (2-pyridyl) -fenchyl alcohol was obtained by the procedure of Example I using dl-fenchone as the ketone. The product was collected at 105-110 C./0.2 mm.; M. P. 54-56 C. The hydrochloride melted at 200-202" C. (dec.). This carbinol (58 grams) was converted to the fi-dimethylaminoethyl ether; B. P. -138 C./0.2 mm. by the procedure of Example I. The hydrochloride melted at 197-198 C.

The p-diethylaminoethyl ether prepared in the same way from fl-diethylaminoethyl chloride had a B. P. of 150-56/0.2 mm. and gave a hydrochloride melting at 192-94.

Example VIII .-2- (Z-pyridyl) -2- (p-dimethylaminoethory) cyclohexane.a- (Z-pyridyl) -cyclohexanol was obtained by using cyclohexanone as the ketone in the procedure of Example I. It was collected at -145/12 mm. Its hydrochloride melted at 157-59 C. corr. This carbinol was converted to the amino ether by the procedure of Example I to give the base of B. P. 13942 C./1 mm. The dihydrochloride had a M. P. of 163-164".

Example IX.-1 (Z-pyridyl) -1 (Z-fi-dz'methylaminoethowy) indane.-1-(2-pyridyl) 1 indanyl alcohol, distilling at PLO-144 C./0.3 mm. was prepared by the procedure of Example I, using a-hydrindone as the ketone. The hydrochloride melted at 154-156 C. This carbinol was converted by the etherification procedure of Example I to the aminoether, which distilled at 162-164" C./0.3 mm. The monohydrochloride melted at 137-139 C.

We claim:

1. The compounds of the generic formula:

in which R is selected from the group consisting of the hydrogen atom and alkyl radicals havin from 1 to 2 carbon atoms, R" is selected from the group consisting of the hydrogen atom and alkyl radical having from 1 to 2 carbon atoms,

n is an integer from 1 to 3, NR2 is selected from the group consisting of dimethylamino, diethylamino, methylethylamino, 4-morpholine, 1- piperidino and l-pyrrolidino and 6. 2-(2-a-picoly1) 2 -(B-diethy1aminoethoxy) 1,3,3-trimethylnorcamphane.

ROBERT S. SHELTON. CHARLES H. TILFORD.

No references. 

1. THE COMPOUNDS OF THE GENERIC FORMULA: 